Summary of work: In the past year we have continued to expand on previous investigations of cardiovascular and diabetes disease risk. We had previously reported that young male monkeys on calorie restriction (CR) exhibited reduced serum lipids and increased levels of HDL2B. Low levels of this HDL subfraction have been associated with increased cardiovascular disease risk in humans. Most recently, we showed that both male and female monkeys on CR have less blood pressure, cholesterol, and triglyceride levels, compared to monkeys eating ad libitum. We have also shown that, in male monkeys, CR improved insulin sensitivity during a frequently sampled glucose tolerance. Another recently completed study showed that CR significantly reduced pulse wave velocity, an index of arterial stiffness, in both young and old monkeys. Taken together these findings suggest strongly that CR will have a beneficial effect on cardiovascular disease and diabetes risk in both male and female monkeys. Work in our laboratory also includes investigation of primate models of menopause and osteoporosis. We have previously shown that rhesus monkeys exhibit age-related declines in bone density that are very similar to those reported in humans. More recently, we have shown that changes in reproductive cycling and hormones in aging female monkeys parallel the human situation. Specifically, female rhesus monkeys begin to exhibit significant menstrual difficulty or cessation of menses after about 24 years of age. Concomitant reductions in estrogen and significantly elevated levels of follicle-stimulating hormone (FSH) were also reported. These findings are in agreement with human data on the perimenopause/menopause transition and support the use of rhesus monkeys as potentially important models of human reproductive aging. Regarding CR, we found that menstrual cycling and reproductive hormones in monkeys on the diet did not differ significantly from controls. We have continued to pursue possible metabolic mechanisms of CR. Using a short-term CR paradigm in monkeys we have shown that insulin and insulin responsiveness are among the first metabolic changes to occur in response to CR. Our preliminary findings show that these changes occur prior to any alteration of body weight or fat suggesting an effect of CR on these parameters that is independent of body composition. We have also recently completed a study designed to test whether administration of a glucose analogue could ?mimic? certain metabolic hallmarks of CR without reducing food intake. Analogue treated rats weighed slightly less, and exhibited significant reductions in body temperature and serum insulin. These important studies showed that maybe its possible to ?mimic CR?, without reducing food intake. They also provided additional support that glucose and insulin metabolism play a central role in the diverse effects of CR.